Epilepsy is a debilitating neurological disorder that affects approximately 50-60 million people worldwide. Unfortunately, only 70% of patients are effectively treated with available anticonvulsant drugs. The goal of this R21 grant application is to characterize unique galantine-based compounds discovered in our laboratory for their ability to treat pharmaco-resistant epilepsy. Galantine is an anticonvulsant neuropeptide that provides a unique opportunity to develop novel antiepileptic drugs, but this peptide exhibits poor metabolic stability and does not penetrate the blood-brain-barrier. Our results suggest that we have successfully designed systemically-active anticonvulsant galantine analogs that are: metabolically and conformationally more stable, AND can penetrate the blood- brain-barrier, AND retain high affinity toward two galantine receptor subtypes. The gain of the systemic bioavailability of the galantine analogs was a result of a judicious combination of several chemical modifications, of which a specific lip amino acid coupled to cationization appeared to be critical components. In the present grant application, we propose to test a hypothesis that by optimizing the length of the critical lip amino acid substituent, we will improve systemic activity of the galanin analogs, without affecting receptor binding properties. Correlations between the length of the lipoamino acid and several physico-chemical and functional parameters will be used to dissect a role of metabolic stability, lipophilicity and conformation in improving systemic bioavailability of the galanin analogs, thus providing an important mechanistic insight into how the lipoamino acid may increase systemic activity of these unique anticonvulsant peptides. PUBLIC HEALTH RELEVANCE: This project aims to advance a greater understanding of the role of galanin and their receptors in epilepsy. We propose to synthesize a series of unique antiepileptic compounds that can access critical parts of the brain responsible for the initiation and propagation of seizure activity. Such compounds will be used to study the mechanisms of seizures in epilepsy and ultimately to a novel therapeutic strategy for preventing, slowing or halting the development of epilepsy.